On February 4, 2016 Seattle Genetics, Inc., (Nasdaq: SGEN) reported that it will receive a one-time $20 million milestone payment under its ADCETRIS (brentuximab vedotin) collaboration with Takeda Pharmaceutical Company Limited (Takeda) (Press release, Seattle Genetics, FEB 4, 2016, View Source [SID:1234508973]).

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The milestone was triggered by Takeda surpassing annual ADCETRIS net sales of $200 million in its territory during 2015. The milestone will be recognized as royalty revenue in the first quarter of 2016. In addition, the company announced that the European Commission recently approved a Type II variation that includes data on the retreatment of adult patients with relapsed or refractory (R/R) Hodgkin lymphoma or R/R systemic anaplastic large cell lymphoma (sALCL) who previously responded to ADCETRIS and who later relapse. The label update follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in October 2015.

"This sales milestone and recent label update in Europe to include data on retreatment underscore the strong commercial and regulatory progress that Takeda has made in its territory," said Clay B. Siegall, Ph.D., President and Chief Executive Officer at Seattle Genetics. "We and Takeda are focused on the goal of establishing ADCETRIS as the foundation of care for CD30-expressing lymphomas through global commercialization activities and a broad clinical development program that includes three phase 3 trials."

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics is entitled to royalties based on a percentage of Takeda’s net sales in its territory at rates that range from the mid-teens to the mid-twenties based on sales volume subject to offsets for royalties paid by Takeda to third parties. In addition, Seattle Genetics is entitled to receive progress- and sales-dependent milestone payments based on net sales of ADCETRIS within Takeda’s licensed territory. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About ADCETRIS (Brentuximab Vedotin)
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily. In HL, CD30 may be involved in tumor cell proliferation by interacting with immune cells in the tumor microenvironment.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. In January 2016, the European Commission approved a Type II variation to include data on the retreatment of adult patients with Hodgkin lymphoma or sALCL who previously responded to ADCETRIS and who later relapse. ADCETRIS has received marketing authorization by regulatory authorities in 60 countries. See important safety information below.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS (brentuximab vedotin).

Contraindication
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.

Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.

Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.

Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.

Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary Toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.

Most Common Adverse Reactions:
ADCETRIS was studied as monotherapy in 160 patients with relapsed classical HL and sALCL in two uncontrolled single-arm trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. The most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:
MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at View Source

On February 4, 2016 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops novel anticancer therapeutics using its ADC technology, and Merck, known as MSD outside the United States and Canada, reported that they have entered into a clinical research collaboration for the assessment of ImmunoGen’s mirvetuximab soravtansine in combination with Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab), for the treatment of patients with FRα-positive ovarian cancer (Press release, ImmunoGen, FEB 4, 2016, View Source [SID:1234508972]).

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Mirvetuximab soravtansine is an experimental ADC for FRα-positive cancers that has shown notable activity for FRα-positive ovarian cancer in early clinical testing. Mirvetuximab soravtansine contains a monoclonal antibody that enables it to bind to FRα-positive tumor cells with ImmunoGen’s DM4, a maytansinoid cancer-killing agent, attached to kill these cells. In preclinical research conducted by ImmunoGen and academics, ADCs with maytansinoids have been found to enhance the maturation and activation of the dendritic cells of the immune system that stimulate antitumor responses.1,2 Keytruda is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Keytruda blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T-lymphocytes, which may affect both tumor cells and healthy cells.

"We look forward to evaluating our mirvetuximab soravtansine ADC in combination with Merck’s anti-PD-1 therapy, Keytruda," said Daniel Junius, ImmunoGen President and Chief Executive Officer. "In early clinical testing, mirvetuximab soravtansine has demonstrated notable activity as a single agent for FRα-positive ovarian cancer, and we are aggressively advancing it for this use. At the same time, we believe mirvetuximab soravtansine should be evaluated in different combination regimens to potentially provide the greatest benefit to the most patients. Keytruda has a different mechanism of action than the other agents being assessed."

"Fully realizing the potential for Keytruda to help patients with cancer requires strategic collaborations, such as this agreement with ImmunoGen, that explore how complementary approaches might result in improved outcomes for patients," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "We look forward to evaluating the data from this combined approach in patients with FRα-positive ovarian cancer."

ImmunoGen is conducting a Phase 1b/2 clinical trial, FORWARD II, that evaluates mirvetuximab soravtansine for FRα-positive ovarian cancer used in doublet combination with other anticancer agents. The assessment of mirvetuximab soravtansine with Keytruda will be added to this trial, with Merck supplying the Keytruda. ImmunoGen expects this cohort to open for patient enrollment in the second half of 2016.

The agreement is between ImmunoGen and Merck, through a subsidiary. The agreement includes a provision for potential expansion of the collaboration to include a subsequent Phase 3 clinical trial. Additional details were not disclosed.

About Mirvetuximab Soravtansine

ImmunoGen developed mirvetuximab soravtansine as a potential treatment for ovarian cancer and other FRα-positive solid tumors. In early clinical testing, mirvetuximab soravtansine demonstrated notable activity when used as a single agent to treat platinum-resistant FRα-positive ovarian cancer.3 ImmunoGen is assessing the ADC used as a single agent for pretreated FRα-positive ovarian cancer in its Phase 2 trial, FORWARD I, which is intended to support an Accelerated Approval pathway. Mirvetuximab soravtansine is also now being assessed in separate combinations with pegylated liposomal doxorubicin (Doxil), bevacizumab (Avastin), and carboplatin in the Phase 1b/2 trial, FORWARD II.

About Ovarian Cancer

Each year there are approximately 240,000 new cases of ovarian cancer diagnosed and 140,000 deaths from the disease on a global basis.4 Among all gynecologic cancers, ovarian cancer accounts for the most deaths on an annual basis.

On February 4, 2016 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that Cancer Research UK has initiated a new, investigator-sponsored Phase 1/1b clinical trial of a combination of paclitaxel with taladegib – the company’s novel, orally available, hedgehog/smoothened inhibitor – in patients with platinum-resistant, recurrent ovarian cancer or recurrent, advanced solid tumors (Press release, Ignyta, FEB 4, 2016, View Source [SID:1234508971]).

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This clinical trial is an open label dose-escalation and expansion study designed to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), tolerability, pharmacokinetics and preliminary clinical activity of the combination of taladegib and weekly paclitaxel in this patient population. The lead investigator will be Dr. Rosalind Glasspool of the Beatson West of Scotland Cancer Centre, Glasgow, Scotland.

"We are excited that Cancer Research UK has expanded the clinical investigation of taladegib through the initiation of this combination study"

"We are excited that Cancer Research UK has expanded the clinical investigation of taladegib through the initiation of this combination study," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "We look forward to supporting Cancer Research UK in this trial, and to evaluating the data, including potentially identifying the impact of this therapeutic intervention on the hedgehog pathway at both the mRNA and protein levels and correlating these changes with the patients’ disease and potential clinical response."

About Taladegib

Taladegib, which Ignyta exclusively licensed from Eli Lilly and Company in November 2015, is a potent, orally bioavailable small molecule hedgehog/smoothened antagonist that has achieved clinical proof-of-concept and a recommended Phase 2 dose based on results from prior clinical studies. Ignyta believes taladegib represents a potential first-in-class hedgehog/smoothened inhibitor for second-line treatment of locally advanced or metastatic basal cell carcinoma, as well as a potential best-in-class hedgehog/smoothened inhibitor for first-line treatment of these patients. In addition, Ignyta believes taladegib alone or in combination has the potential to treat selected patients with solid tumors outside of basal cell carcinoma that are driven by hedgehog pathway alterations. Ignyta also granted back to Lilly exclusive rights for Lilly to develop and commercialize taladegib-containing products in combination with certain Lilly compounds.